Hemoglobinpathies Flashcards
(42 cards)
what are the thalassemias?
pathologies characterized by deficiencies in globin chain production (& sometimes a compensatory inc in the other chain)
- alpha thalassemia
- beta thalassemia
alpha-thalassemia
- pathogenesis?
- variations?
caused by a deletion of one or all of the four alpha chain genes
- four deletion patterns
- loss of 1 gene - no problem
- loss of 2 genes - minor changes (anemia)
- loss of 3 genes = HbH disease
- formation of B4 tetramers
- severe anemia
- loss of 4 genes = HbBarts
- fatal in utero
- formation of y chain tetramers
- hydrops fetalis
- fatal in utero
in what regions is alpha thalassemia prevalent? why is this is the case?
malaria belt - Southeast Asia, Middle East > Africa, Mediterranean
HbH presentation
= alpha thalassemia d/t 3 gene deletions
-
presence of B-chain tetramer (black arrows)
- cause precipitation in erythrocytes → hemolytic anemia
HbBarts presentation
alpha thalassemia d/t 4 gene deletions
-
y chain tetramer
- holds oxygen extremely tightly, cannot deliver it to fetus →
- hydrops fetalis
- death
- holds oxygen extremely tightly, cannot deliver it to fetus →
beta thalassemia
- pathogenesis
- variations
- can be d/t to variety of mutations =- missense, slice, site, promotor, ect
- variations = based on decreasing amount of B-globin
- minor
- intermedia
- major
in what regions is beta thalassemia prevalent?
malaria belt - Southeast Asia, Middle East > Africa, Mediterranean
(same as alpha-thalassemia)
beta thalassemia - presentation
-
alpha-chain tetramers form → dyserythropoiesis →
- overworked spleen
- splenomegaly
- skeletal abnormalities
- long bones
- altered skull / maxilla
- overworked spleen
identify the cause & explain
splenomegaly d/t beta-thalassemia
- alpha globins are less soluble than beta globins. alpha 4 tetramers aggregate in RBCs → damaged RBCs overwork the spleen → spleen hypertrophies → splenomegaly
identify the cause & explain
skeletal abnormalities d/t beta thalassemia
- alpha globins are less soluble than beta globins. alpha 4 tetramers aggregate in maturating RBCs in bone marrow → bone marrow damage
- long bones
- abnormally shaped skull maxilla (flat skull)
in what hemoglobinopathies might blood smears show teardrop RBCs?
- thalassemias
- fibrosis disorders
what are the point mutation hemoglobinopathies?
hemoglobinopathies arising from single point mutations in globin gene
- HbS (sickle cell anemia)
- HbC
- HbD, HbE, ect.
sickle cell anemia - pathogenesis
- point mutation hemoglobinopathy
- Glu → Val at position 6
- Val, a hydrophobic aa, interacts with hydrophobic patches on adjacent Hb →
- RBC aggregation, membrane disruption, abnormal cell shape / size
how does sickle cell anemia alter RBC membrane transport?
- inc K+Cl- cotransport out of cell & INC intracellular [Ca+]. leads to
- intracellular H20 decrease & relative HbS increase → abnormal RBC size/shaoe
how does sickle cell anemia affect membrane composition?
- several structural changes:
- presence of CAMs (cell-adhesion molecules)
- change in orientation PL / membrane protein orientation
- cytoskeletal deformation
- all of which lead to
- inc interaction of RBC with vascular endothelium
- prothrombotic RBCs
the altered composition of RBC membranes in sickle cell anemia leads to what major consequences?
- produces RBCs that
- interact with vascular endothelium more
- are pro-thrombotic
in what regions is sickle cell anemia most prevalent? why?
in those with endemic _falciparum_ malaria: sickle cell heterozygotes survive malaria, pass on genes
describe a blood smear from someone with sickle cell anemia
- RBCs can can be
- normocytic / normochromic, or
- show
- poikilocytosis (abnormal shape)
- anisocytosis (size variation)
summarize the clinical presentation of sickle cell anemia
presentation is d/t hemolysis (hyper-bilirubinemia) & RBC aggregation (splenic sequestration):
- splenic sequestration → splenic infarctions / auto-splenectomy / pain crisis
- hyperbilirubinemia → jaundice / bilirubin gallstones
- in children → edema of hands and feet
what is splenic sequestration?
in what kind of anemia does if manifest?
phenomenon seen in sickle cell anemia.
characterized by presence of a large # of damaged RBCs in splenic capillaries, which can lead to
- splenic infarction
- low hematocrit (low# of circulating blood cells)
tx of splenic sequestration
transfusion.
though it will alleviate the sx of anemia, one must done carefully, such that hematocrit is not to high once sequestration ends
dx of sickle cell anemia?
two methods
- southern blot: shows disruption of MST-II cleavage site
- ASO: shows T→ A missense mutation - modern, commonly used method
how is a southern blot used to dx sickle cell anemia?
-
it reveals disrupted Mst-II site
- in HbS, the Glu → Val mutation disrupts cleavage site Mst-II. this missed cleavage results in a longer mutant chain (1.3 kb) as opposed to the 1.1 kb B-chain seen in Hb.
- two 1.1 kb fragments = normal
- one 1.1 kb fragment + one 1.3 kb fragment = heterozygous (carrier)
- two 1.3 kb fragments = HbS
- in HbS, the Glu → Val mutation disrupts cleavage site Mst-II. this missed cleavage results in a longer mutant chain (1.3 kb) as opposed to the 1.1 kb B-chain seen in Hb.
